Post-acute COVID-19 symptom risk in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis

Background Post-acute coronavirus disease 2019 (COVID-19) symptoms occurred in most of the COVID-19 survivors. However, few studies have examined the issue of whether hospitalization results in different post-acute COVID-19 symptom risks. This study aimed to compare potential COVID-19 long-term effects in hospitalized and non-hospitalized COVID-19 survivors. Methods This study is designed as a systematic review and meta-analysis of observational studies. A systematic search of six databases was performed for identifying articles published from inception until April 20th, 2022, which compared post-acute COVID-19 symptom risk in hospitalized and non-hospitalized COVID-19 survivors using a predesigned search strategy included terms for SARS-CoV-2 (eg, COVID, coronavirus, and 2019-nCoV), post-acute COVID-19 Syndrome (eg, post-COVID, post COVID conditions, chronic COVID symptom, long COVID, long COVID symptom, long-haul COVID, COVID sequelae, convalescence, and persistent COVID symptom), and hospitalization (hospitalized, in hospital, and home-isolated). The present meta-analysis was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement using R software 4.1.3 to create forest plots. Q statistics and the I2 index were used to evaluate heterogeneity in this meta-analysis. Results Six observational studies conducted in Spain, Austria, Switzerland, Canada, and the USA involving 419 hospitalized and 742 non-hospitalized COVID-19 survivors were included. The number of COVID-19 survivors in included studies ranged from 63 to 431, and follow-up data were collected through visits in four studies and another two used an electronic questionnaire, visit and telephone, respectively. Significant increase in the risks of long dyspnea (OR = 3.18, 95% CI = 1.90–5.32), anxiety (OR = 3.09, 95% CI = 1.47–6.47), myalgia (OR = 2.33, 95% CI = 1.02–5.33), and hair loss (OR = 2.76, 95% CI = 1.07–7.12) risk were found in hospitalized COVID-19 survivors compared with outpatients. Conversely, persisting ageusia risk was significantly reduced in hospitalized COVID-19 survivors than in non-hospitalized patients. Conclusion The findings suggested that special attention and patient-centered rehabilitation service based on a needs survey should be provided for hospitalized COVID-19 survivors who experienced high post-acute COVID-19 symptoms risk.

. Introduction COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has the characteristics of strong contagion and high mortality (1, 2). As of May 16th, 2022, there have been 519 million cumulative confirmed cases resulting from the COVID-19 pandemic according to the live world statistics released by the World Health Organization. With the continuing growth of infected cases across the world, the complication and sequelae of COVID-19 have gradually attracted the attention of health professionals (3). The sequelae of COVID-19 can last several weeks or months, which is also called the post-acute COVID-19 symptom (PACS). Evidence shows that SARS-CoV-2 infection causes direct damage to multi-organs and one or more organ impairments presented in almost 70% of 201 patients (4). Alkodaymi et al. (5) have conducted a systematic review and meta-analysis of 63 studies and 257, 348 COVID-19 survivors and stated most of the patients experienced PACS for at least 3 months after recovery from COVID-19 infection. A crosssectional observational study by Tabacof et al. (6) investigated the influences of PACS on physical and cognitive function, quality of life, and usual activity, which found that PACS had a multifaceted impact on the lives of 156 COVID-19 survivors almost one year after infection.
SARS-CoV-2 can cause various degrees of damage to the respiratory system and extrapulmonary organs such as the immune system, digestive system, cardiovascular system, and nervous system (7,8). Even if the clinical symptoms of patients disappear, most of the patients still have sequelae (9). The number of estimated PACSs after initial recovery can be reached 55 in 80% of 47, 910, and the five frequently reported PACSs were dyspnea, headache, fatigue, attention disorder, and hair loss according to the systematic review and meta-analysis by Lopez-Leon et al. (10). Presently, the prevalence of PACSs has been widely investigated, while the risk factors provoking the development of PACSs have been little studied. A systematic review and meta-analysis by Maglietta et al. (11) stated that female sex and acute disease severity were two risk factors for the development of one or more PACSs. However, the development of PACSs is still not yet comprehensively studied as it affects COVID-19 survivors who are not hospitalized. A cohort study by Petersen et al. (12) assessed the multi-organ functions between non-hospitalized populations after SARS-CoV-2 infection and healthy individuals and stated that the subclinical multiorgan affection signs related to respiratory, cardiovascular, vascular, and renal system organs were identified. In another cohort study comprising 176 hospitalized and 72 non-hospitalized individuals after SARS-CoV-2 infection, PACSs were more frequently presented in hospitalized COVID-19 survivors (13). But the loss of taste was more commonly presented in non-hospitalized COVID -19 survivors (14).
The data of these published studies just focused on some PACSs risk analysis, which did not provide a comprehensive analysis between hospitalized and non-hospitalized non-hospitalized.
Therefore, we conducted the present systematic review and metaanalysis to compare PACSs risk between hospitalized and nonhospitalized patients for providing the theoretical basis to develop PACS rehabilitation services.

. Materials and methods
The present study was designed to compare post-acute COVID-19 symptom risk in hospitalized and non-hospitalized COVID-19 survivors. We conducted the present meta-analysis following The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, checked and confirmed that the recommended items of the PRISMA 2020 statement were reported in the present meta-analysis (15).

. . Inclusion and exclusion criteria
To be included in the present meta-analysis there were a set of inclusion criteria that studies would be required to fulfill. The inclusion criteria were specified as follows: (1) population: included subjects who suffered SARS-CoV-2 that diagnosed by polymerase chain reaction (PCR) testing and followed up for at least 12 weeks; (2) Intervention: hospitalization as the baseline exposure; (3) Comparison: non-hospitalized COVID-19 survivors as a control; (4) Outcomes: reported PACS prevalence and the corresponding 95% confidence intervals of hospitalized COVID-19 survivors relative to those non-hospitalized; (5) Study design: prospective or retrospective observational studies which have no restriction of sample size. For multiple results obtained by observing the same participants over different lengths of time, only the latest published results with the longest observation period were included. The exclusion criteria were: (1) studies with a follow-up period of fewer than 12 weeks; (2) reviews, meta-analyses, case reports, conference abstracts, or animal trials; (3) studies without complete data for data synthesis; (4) duplicated articles or data. For multiple results obtained by observing the same participants over different lengths of time, only

. . Literature screening
The retrieved records of four databases that fulfilled the eligibility criteria were downloaded and independently screened by two coauthors who contributed to the literature screening. In case of disagreement, a consensus would be reached through discussion. If no consensus could be reached, the decision would be made by rereview of another two co-authors. During literature screening, the titles and abstracts were first to be read to exclude irrelevant studies. The full texts were further read to determine whether to include the study.

. . Data extraction
The data were systematically abstracted from included study containing the first author's family name, year of publication, study design, the country where the study was carried out, number and age of included COVID-19 survivors, follow-up mode and length, symptoms of PACS, and effect estimates of prevalence. Data extraction in the present meta-analysis was conducted by two coauthors. In case of discrepancies, a discussion is needed, and when necessary, the decision is reached by another two co-authors.

. . Quality assessment
The quality assessment of the included studies was carried out by two co-authors using the Newcastle-Ottawa Scale (17), which was widely used in the previous systematic review for prospective and retrospective observational studies on the topic of COVID- 19 (18, 19). This nine-point scale consists of 8 items in three dimensions: selection, comparability, and outcome. Selection, comparability, and outcome of cohorts containing 4, 1, and 3 items with 4, 2, and 3 scores respectively. In case of discrepancies, a discussion is needed, and when necessary, the decision is reached by another two co-authors.

. . Statistical analysis
To compare PACS risk between hospitalized and nonhospitalized COVID-19 survivors, the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with raw data using R software 4.1.3. Heterogeneity among studies was assessed using Cochrane's Q-test (with P > 0.1 indicating heterogeneity) and the I 2 statistic (where I 2 ≥ 50% indicated significant heterogeneity). The random or fixed effects model was chosen and applied for data synthesis according to the results of heterogeneity. Sensitivity analyses by removing studies one at a time were conducted for all indicators to evaluate the stability of pooled results. Publication bias was assessed using funnel plots (asymmetrical funnel plot indicated a significant publication bias) and Egger's test (with P < 0.05 indicated a significant publication bias). . Results

. . Study selection
A total of 4004 records were yielded from searching six databases, by which 2,033 duplicated studies were excluded. After screening the title and abstract of the remaining 1,971 records, 11 potentially included studies identified for full-text review. Three studies were excluded because intervention measures are not compliant (20-23); another two studies were excluded because the result indicator does not match (24, 25). In the last, a total of 6 studies were included in the present meta-analysis (Figure 1).

. . Sensitivity analysis and publication bias
The stability of the pooled result was assessed by sensitivity analysis. The results of sensitivity analysis of OR for PACSs risk comparing hospitalized and non-hospitalized COVID-19 survivors showed no significant heterogeneity (Supplementary Figures 1A-L). The publication bias of the pooled result was evaluated by constructing funnel plots and performing Egger's test when the number of included studies was equal to or more than 3. The results of funnel plots and Egger's test suggested little evidence of publication bias for any persistent symptom, fatigue, dyspnea, headache, and myalgia risk comparing hospitalized and nonhospitalized COVID-19 survivors ( Supplementary Figures 2A-E).

. Discussion
The present systematic review and meta-analysis summarized the association of hospitalization and PACSs among COVID-19 survivors from six studies. These six studies were of moderate to high quality. Because the pooled risk generated was based on crude estimates, these findings need to be interpreted with caution.
. /fpubh. .  (OR = 3.18, 95% CI = 1.90-5.32), anxiety (OR = 3.09, 95% CI = 1.47-6.47), myalgia (OR = 2.33, 95% CI = 1.02-5.33), and hair loss (OR = 2.76, 95% CI = 1.07-7.12) risk was found in hospitalized COVID-19 survivors compared with outpatients. Evidence on why PACSs occur is still largely unknown, however, numerous studies have confirmed that PACSs developed regardless of the initial disease severity (30). Respiratory symptoms lasting over 28 days were commonly reported among 4,182 COVID-19 survivors in a prospective cohort study (31). A multicenter crosssectional study by Mandal et al. (32) stated that CT lung abnormalities were found among 38% of COVID-19 survivors after discharge from the hospital at a median follow-up time of 54 days. Another prospective study carried out by Vijayakumar et al. (33) also investigated the imaging abnormalities in COVID survivors after hospital discharge at a longer median follow-up time of 105 days and found that 56% of patients presented with persistent CT lung abnormalities mainly characterized as ground-glass opacification and irregular bands. Whist lung impairment was another concern among COVID-19 survivors. A systematic review and meta-analysis conducted by Torres-Castro et al. (34) summarized the prevalence of lung impairment in COVID-19 survivors and found that diffusion capacity was predominating. The influencing factors for diffusion impairment at 180 days after hospital discharge were female sex, age, and peak RALE score (35). Dyspnea, cough, and chest pain have been proven to be the predominant persistent respiratory symptoms (36). Our findings indicated a significant increase in dyspnea risk among hospitalized COVID-19 survivors compared with non-hospitalized. A multicenter prospective study by Bretas et al. (37) demonstrated that the prevalence of dyspnea was as high as 64.7% in ward admission. The potential reason why high dyspnea risk presented in hospitalized COVID-19 survivors compared with non-hospitalized is COVID-induced persistent abnormality within the microstructure of the lungs or in the pulmonary vasculature (38).
Significant differences in neurological symptoms (ageusia and anxiety) risk between hospitalized and non-hospitalized were found in this meta-analysis. According to a cross-sectional study by Sampaio Rocha-Filho et al. (39), ageusia was a dominant persistent neurological symptom among 288 COVID-19 survivors with a high occurrence rate of 69.8%. However, another prospective followup study by Nielsen et al. (40) stated that the prevalence of long-lasting ageusia was highly increased among mild COVID-19 survivors, which is consistent with our findings that persisting ageusia risk is significantly decreased in hospitalized individuals compared with non-hospitalized populations after SARS-CoV-2 infection. This above result might be associated with the pathological basis of neurotropic infection in the gustatory system (41). A metaanalysis of 19 studies has demonstrated that anxiety was a frequent neuropsychiatric manifestation among COVID-19 survivors (42). Whist, anxiety was a common persistent neurological symptom among most of the non-hospitalized COVID-19 survivors (43). Our meta-analysis revealed a high prevalence of anxiety in hospitalized compared with non-hospitalized COVID-19 survivors. The mechanism related to anxiety risk include systemic inflammation response to SARS-CoV-2 infection and perceived stress before and during COVID-19 infection (44).
High risks of other symptoms containing myalgia and hair loss have been identified among hospitalized compared with nonhospitalized COVID-19 survivors in the present meta-analysis. A previous scoping review by Cha  The present systematic review and meta-analysis is the first time to compare PACSs risk in hospitalized and non-hospitalized COVID-19 survivors. However, there are several limitations existed in this study. Firstly, the included studies have a restriction on the published language of Chinese or English. Secondly, five of the six studies were single-center prospective studies with limited sample sizes. Thirdly, heterogeneity differences in the outcomes of fatigue and depression risks of the included studies were another crucial limitation in this meta-analysis. Finally, the PACS risks were compared between hospitalized and non-hospitalized COVID-19 survivors at different lengths of follow-up time, which may significantly influence the results.

. Conclusion
In conclusion, the present meta-analysis has provided a comprehensive analysis of PACSs risk between hospitalized and non-hospitalized COVID-19 survivors. It showed that those in hospitalization experienced high post-acute COVID-19 symptoms risk such as dyspnea, anxiety, myalgia, and hair loss, and a low risk of persisting ageusia. Health professionals should pay special attention to PACSs risk for hospitalized COVID-19 survivors and provide patient-centered rehabilitation services. Moreover, Health professionals could develop assessment tools of high quality to evaluate persisting dyspnea, ageusia, anxiety, myalgia, and hair loss risk, especially for hospitalized COVID-19 survivors. Meanwhile, the need for a patient-centered strategy for long-COVID care is urgent that should be investigated.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.